Abstract
Purpose:
Immunotherapy (IO) in triple negative breast cancer (TNBC) has improved survival outcomes, with promising improvements in pCR rates among early high-risk HR+/HER2− breast cancers. However, biomarkers are needed to select patients likely to benefit from IO. MHC-I and tumor-specific MHC-II (tsMHC-II) expression are candidate biomarkers for PD-(L)1 checkpoint inhibition, but existing data from clinical trials included limited racial/ethnic diversity.
Methods:
We performed multiplexed immunofluorescence assays in the Carolina Breast Cancer Study (CBCS, n=1628, 48% Black, 52% non-Black). Intrinsic subtype and P53 mutant-like status were identified using RNA-based multigene assays. We ranked participants based on tumoral MHC-I intensity (top 33% categorized as “MHC-IHigh”) and MHC-II+ (≥5% of tumor cells as tsMHC-II+). MHC-I/II were evaluated in association with clinicopathological features by race.
Results:
Black participants had higher frequency of TNBC (25% vs. 12.5%, p = < 0.001) and Basal-like (30% vs. 14%, p = < 0.001) tumors overall, and higher frequency of Basal-like (11% vs. 5.5%, p = 0.002) and TP53 mutant tumors (26% vs. 17%, p = 0.002) among HR+/HER2−. The frequency of tsMHC-II+ was higher in HR+/HER2− Black participants (7.9% vs. 4.9%, p = 0.04). Black participants also had higher frequency of MHC-Ihigh (38.7% vs. 28.2%, p <0.001), which was significant among HR+/HER2− (28.2% vs. 22.1%, p = 0.02).
Conclusions:
In this diverse study population, MHC-I and MHC-II tumor cell expression were more highly expressed in HR+/HER2− tumors from Black women, underscoring the importance of diverse and equitable enrollment in future IO trials.
Keywords: major histocompatibility-I, major histocompatibility-II, biomarkers, immunotherapy, breast cancer
Translational relevance statement:
Immune checkpoint inhibitors improve outcomes in subsets of triple negative and HR+/HER2− breast cancer. Nonetheless, most breast cancer patients do not benefit from the addition of immunotherapy, highlighting a pressing need to utilize biomarkers to optimize patient selection. MHC-I and MHC-II expression in tumor cells are candidate biomarkers for predicting ICI response in breast cancer; however, existing data from clinical trials included limited racial/ethnic diversity, which has biological and tumor phenotyping implications. Using a racially balanced patient cohort, we evaluated the MHC-I/II expression in association with clinicopathological features by race. We observed higher tumoral MHC-I and MHC-II expression in HR+ Black patients compared to White patients, strengthening the discussion and need for racially inclusive immunotherapy clinical trials.
Introduction:
Immunotherapy is now the standard of care for high-risk early triple-negative breast cancer (TNBC) based on the improvements in event-free survival (EFS) seen with the combination of anti-PD-1 antibodies and chemotherapy for locally advanced TNBC.1,2 Recent studies have now also shown improved pathological complete response (pCR) rates with chemoimmunotherapy in early high-risk HR+/HER2− breast cancer,3–5 particularly in tumors with low and moderate ER expression, with EFS outcomes forthcoming. However, improved outcomes come at the cost of considerably increased toxicity, highlighting a critical need for biomarkers to select patients that are more likely to benefit from immunotherapy.
Tumor major histocompatibility complex I and II (MHC-I and MHC-II) present tumor antigens to T cells, a process required for the mechanism of action of immunotherapy and have both shown promise as potential biomarkers of anti-PD-(L)1 benefit. MHC-I loss is associated with a lack of response to immunotherapy.6,7 In addition, in a Phase II trial of metastatic TNBC participants treated with carboplatin + atezolizumab, only patients with tumors with high MHC-I expression demonstrated significant improvement in progression-free survival. Even more well-studied, tumor-specific MHC-II (tsMHC-II) expression is associated with increased pCR and EFS after neoadjuvant therapy regimens containing anti-PD-(L)1 agents in breast cancer and other immunotherapy-responsive cancers like melanoma.8–10 As such, tsMHC-II is currently under evaluation as a planned integrated biomarker on multiple prospective phase III clinical trials.
Despite the observation that Black women have a higher prevalence of both TNBC and high-risk HR+/HER2− breast cancer, most immunotherapy clinical trials in breast cancer, including those reporting on biomarkers, have historically had low representation of Black patients or did not report on race3–5. Prior studies have shown similar response rates to neoadjuvant regimens including chemotherapy and anti-PD-(L)1 agents across racial/ethnic groups in women with high-risk HER2− breast cancers.11,12
As immunotherapy becomes increasingly relevant for breast cancer, a disease that is diagnosed in almost 300,000 women annually in the United States,13 it is imperative that we incorporate biomarkers that have been evaluated across diverse racial/ethnic groups. The potential of MHC-I and tsMHC-II as biomarkers for predicting benefit with the addition of anti–PD-(L)1 immunotherapy to standard chemotherapy in HER2− breast cancer has been established.8 We sought to determine associations between MHC-I and tsMHC-II positivity and clinicopathological features in a diverse cohort.
Methods:
Study Population and molecular features.
The Carolina Breast Cancer Study (CBCS) is a population-based study conducted in North Carolina (NC) that began in 1993. Briefly, cases of invasive breast cancer between age 20 and 74 years were identified using rapid case ascertainment in cooperation with the NC Central Cancer Registry, with black and young cases (age 20–49 years) oversampled using randomized recruitment. Study details and sampling schemes have been described previously.14 Race was determined by self-reporting and categorized as Black or non-Black. The CBCS has adopted a Cells to Society Framework for understanding racial differences, which acknowledges that race is a social construct influenced by many factors including ancestry, individual behavioral factors, social factors, and structural advantages and disadvantage.15 Intrinsic subtype and P53 mutant-like status were identified using RNA-based multigene assays as previously reported16. Association between molecular features and race was tested using Chi-square test or fisher-exact test.
This project was approved by the institutional review boards of the Lineberger Cancer Center at University of North Carolina and of the University of Washington. Participants in the CBCS signed written informed consent at enrollment, including for use of their DNA. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820260/
MHC-I and MHC-II analysis.
Immunofluorescent assays for cytokeratin (CK), MHC-I (HLA-A/B/C) and MHC-II (HLA-DR) were developed and optimized using tyramide signal amplification as previously described.8,17 Formalin-fixed paraffin embedded tissue sections from 88 TMAs containing samples from 1670 patients were stained with the following primary antibody: HLA-DR TAL1B5 Santa Cruz at 1:1000, panCK Z0622 Dako at 1:1300, HLA-A/B/C C6 Santa Cruz at 1:1,300. Whole-slide images were digitally acquired using an AxioScan Z1 slide scanner (Carl Zeiss) at 20x. Automated quantitative scoring was performed by a pathologist blinded to sample characteristics, using QuPath software. Briefly, object classifiers were trained on annotated training regions from control tissue and tumor samples to define cellular phenotypes as previously described.8,17 Each core was visually assessed for correct performance of the quantification algorithm.
To evaluate MHC-I all participants were ranked based on tumoral MHC-I intensity, with the top 33% categorized as “MHC-IHigh”. MHC-II expression on tumor cells was considered as ≥5% of tumor cells based on prior experience.8 Relative frequency difference was calculated using R package risks (v0.4.2), using marginal standardization for model fitting.
Data availability.
Existing CBCS data are available upon request (https://unclineberger.org/cbcs). MHC-I, MHC-II quantification and images, as well as an R code/script for data analysis is available upon email request to justin.balko@vumc.org.
Results:
Participant characteristics.
The study included 1628 participants (48% Black and 52% non-Black) with Stage I-III breast cancer (Table 1). Less than 6% of the non-Black participants were non-White, and therefore were not separated from the White participants for analysis. The Non-Black population contained 8 American Indian or Eskimo, 18 Asian or Pacific Islander, 29 cases documented as Other, and 789 White. The median (IQR) age at breast cancer diagnosis was 52 (44–61) and 52 (45–63) for Black and non-Black participants, respectively. Stage at diagnosis did not differ by race (87% vs. 89%, with relative frequency difference [RFD] = −1.32% (95% CI: −4.47%, 1.87%), p=0.4 for Black compared to Non-Black participants). Black participants had a higher frequency of TNBC (25% vs. 12.5%, RFD = 12.32% (95% CI: 8.57%, 16.06%), p=<0.001), and a higher frequency of basal-like (30% vs. 14%, RFD = 15.51% (95% CI: 10.77%, 20.25%), p=<0.001) and transcriptionally TP53-mutant-like tumors (49% vs. 29%, RFD = 20.05% (95% CI: 14.56%, 25.53%), p=<0.001). In the HR+/HER2− subgroup, Black participant tumors were more frequently Basal-like (11% vs. 5.5%; RFD = 5.5% (95% CI: 1.55%, 9.35%), p=0.002) and TP53-mutant-like (26% vs. 17%, RFD = 8.70% (95% CI: 2.90%, 14.5%), p=0.002).
Table 1:
Clinicopathological characteristics of the CBCS cohort by Race
| Characteristics | Race | p-value2 | ||
|---|---|---|---|---|
| Overall N = 1,6281 | Black N = 7841 | Non-Black N = 8441 | ||
| Age | 52 (44, 62) | 52 (44, 61) | 52 (45, 63) | 0.12 |
| Stage | 0.39 | |||
| I/II | 1,430 (88%) | 683 (87%) | 747 (89%) | |
| III | 198 (12%) | 101 (13%) | 97 (11%) | |
| Clinical subtype | <0.001 | |||
| HR+/HER2− | 1,114 (68%) | 467 (60%) | 647 (77%) | |
| HER2+/HR+ | 152 (9.3%) | 86 (11%) | 66 (7.8%) | |
| HER2+/HR− | 62 (3.8%) | 36 (4.6%) | 26 (3.1%) | |
| TN | 300 (18%) | 195 (25%) | 105 (12%) | |
| TP53 RNA | <0.001 | |||
| WT-like | 695 (62%) | 282 (51%) | 413 (71%) | |
| Mut-like | 434 (38%) | 268 (49%) | 166 (29%) | |
| Unknown | 499 | 234 | 265 | |
| PAM50 subtype | <0.001 | |||
| LumA | 570 (50%) | 226 (41%) | 344 (59%) | |
| LumB | 200 (18%) | 106 (19%) | 94 (16%) | |
| Her2 | 75 (6.6%) | 41 (7.5%) | 34 (5.9%) | |
| Basal | 245 (22%) | 163 (30%) | 82 (14%) | |
| Normal | 39 (3.5%) | 14 (2.5%) | 25 (4.3%) | |
| Unknown | 499 | 234 | 265 | |
| PAM50 ROR score | <0.001 | |||
| Low | 313 (28%) | 98 (18%) | 215 (37%) | |
| Intermediate/High | 816 (72%) | 452 (82%) | 364 (63%) | |
| Unknown | 499 | 234 | 265 | |
Median (IQR) or Frequency (%)
Wilcoxon rank sum test; Pearson’s Chi-squared test
MHC-Ihigh and tsMHC-II+ expression in HR+/HER2− tumors.
Overall, Black participants had a higher frequency of MHC-Ihigh tumors (39% vs. 28%; p<0.001). After stratification, the race association was only significant among participants with HR+/HER2− breast cancer (28% vs. 22%; p=0.02) (Figure 1A). Overall, there was a similar distribution of MHC-II+ tumors between Black and non-Black participants, however the relative frequency of tsMHC-II+ tumors was significantly more common in Black participants compared to their non-Black counterparts with HR+/HER2− tumors (8% vs. 5%; p=0.04) (Figure 1B). The distribution of percent positivity across the cohort for both MHC-I and MHC-II is detailed in Supplementary Figure 1. Additionally, MHC-IHigh and MHC-II+ tumors are more prevalent in premenopausal patients (MHC-I: 36.4% vs 30.9%, p=0.03; MHC-II:11.7% vs. 7.0%, p<0.001) and Stage I/II patients (MHC-I: 33.6% vs 31.3%, p=0.13; MHC-II: 9.6% vs. 4.5%, p<0.001) (Supplementary Figure 2 A, B).
Figure 1: MHC-I and MHC-II expression is associated with Race.
The relative frequency difference of tumors having (A) high MHC-I expression (ranked top 33% based on percentage of MHC-I positive tumor) and (B) ≥ 5% tumor cells expressing MHC-II are compared between Black and Non-Black patients. Relative frequency difference calculated using Non-Black as control condition, with positive RFD representing frequency higher in Black patients. Bootstrap method used to generate standard errors.
Association between MHC-Ihigh and tsMHC-II+ expression and PAM50 subtype and TP53 mutations in HR+/HER2− breast cancer.
Patients with Basal-like HR+/HER2− breast cancer had the highest percentage of MHC-Ihigh (67.2%) and tsMHC-II+ (37.7%) tumors, independent of race (Table 2). Among patients with HR+/HER2− breast cancer, patients with Luminal B and Basal-like subtypes were more frequently MHC-Ihigh (RFD = 15.6% and 49.0%, p < 0.001 and p< 0.001) and MHC-II+ (RFD = 4.8% and 34.8, p=0.03 and p < 0.001), compared to Luminal A (Table 2). Furthermore, patients with an intermediate/high PAM50 ROR score were more frequently MHC-Ihigh (RFD = 15.3%, p < 0.001) and MHC-II+ (RFD = 6.6%, p < 0.001), compared to patients with a low PAM50 ROR score (Table 2). In addition, participants with a TP53 mutation had higher frequency of both MHC-Ihigh (RFD = 26.8%, p < 0.001) and MHC-II+ (RFD = 16.9%, p < 0.001). (Table 2).
Table 2: MHC-I and MHC-II expression is associated with tumor molecular features in the HR+/HER2− cohort.
Relative frequency difference of having MHC-I high (left column) or MHC-II+ (right column) tumor is compared across TP53 RNA derived mutation condition (WT-like as control), PAM50 subtype (Luminal A as control), and PAM50 risk of recurrence score(Low as control). Bootstrap method used to generate standard errors.
| Feature | MHC-I low | MHC-I high | RFD (95% CI) | p-value | MHC-II+ <5% | MHC-II+ ≥5% | RFD (95% CI) | p-value |
|---|---|---|---|---|---|---|---|---|
|
|
||||||||
| TP53 RNA * | ||||||||
| WT-like | 494 (80.0%) | 123 (20.0%) | - | - | 598 (96.9%) | 19 (3.1%) | - | - |
| Mut-like | 85 (53.1%) | 75 (46.9%) | 26.8% (18.4, 35.3) | <0.001 | 128 (80.0%) | 32 (20.0 %) | 16.9% (10.5, 23.4) | <0.001 |
| PAM50 subtype ** | ||||||||
| LuminalA | 423 (81.8%) | 94 (18.2%) | - | - | 502 (97.2%) | 15 (2.8%) | - | - |
| LuminalB | 111 (66.0%) | 57 (34.0%) | 15.6% (7.8, 23.5) | <0.001 | 155 (92.3%) | 13 (7.7%) | 4.8% (0.5, 9.2) | 0.03 |
| Basal | 20 (32.8%) | 41 (67.2%) | 49.0% (36.7, 61.1) | <0.001 | 38 (62.3%) | 23 (37.7%) | 34.8% (22.7, 47.0) | <0.001 |
| PAM50 ROR score *** | ||||||||
| Low | 242 (84.0%) | 46 (16.0%) | - | - | 281 (97.5%) | 7 (2.5%) | - | - |
| Inter/High | 337 (69.7%) | 152 (31.3%) | 15.3% (9.4 21.2) | <0.001 | 445 (91.0%) | 44 (9.0%) | 6.6% (3.4, 9.7) | <0.001 |
|
|
||||||||
337 HR+ cases missing TP53 RNA status
339 HR+ cases missing PAM50 subtype, exclude 34 Her2 and Normal like cases
337 HR+ cases missing risk of recurrence score
Discussion:
MHC-I and MHC-II expression was more prevalent in tumors from Black women with HR+/HER2− breast cancer. These results could reflect over-representation of Basal-like or Luminal B tumors among Black women with HR+/HER2− breast cancer, which was observed here and consistent with prior studies14,18–21. Patients with Basal-like HR+/HER2− breast cancer, or those with TP53 mutant-like tumors had the highest percentage of MHC-Ihigh and tsMHC-II+ tumors, independent of race. While there were racial differences in MHC-Ihigh and tsMHC-II+, these seem to correlate with the prevalence of the underlying biological subtypes.
HR+/HER2− Basal-like tumors are biologically similar to TNBC Basal-like tumors with similar immune signatures and pCR rates,22 and the immune landscape of ER low and intermediate tumors mimick TNBC.23 In the HR+/HER2− cohort, Black participants had tumors enriched for a biomarker profile of MHC-Ihigh and tsMHC-II+ tumors, which could reflect greater sensitivity to IO. Moreover, our results corroborate similar findings from an analysis of The Cancer Genome Atlas using an RNA-based MHC-I metagenes, where this marker was also expressed more highly in African American patients vs. Caucasian patients with HR+, but not TNBC24. These results are encouraging given the critical need to develop biomarkers that are generalizable in a diverse population. This emphasizes that inclusion of Black patients on immunotherapy clinical trials is required to define the true potential of immunotherapy when there is an urgent need to reduce racial survival disparities and tailor therapies to improve patient outcomes and limit toxicities.
Future prospective studies incorporating MHC-I and MHC-II are needed to evaluate the correlation of MHC-I/II with survival outcomes in diverse populations with breast cancer, beyond only TNBC. TsMHC-II is currently under evaluation as a planned integrated biomarker on multiple prospective phase III clinical trials evaluating the addition of durvalumab to chemotherapy in the neoadjuvant setting for patients with high-risk ER+ early breast cancer (S2206; NCT06058377) and the addition of pembrolizumab to chemotherapy in the adjuvant setting for patients with TNBC (S1418; NCT02954874). The current study has several strengths including large sample size, substantial representation of Black women, and a novel analysis of MHC-I/II with race in patients with breast cancer. Limitations include the lack of an established clinically-relevant cut point of MHC-I expression in the neoadjuvant setting, and lack of true outcomes to immunotherapy. A more exploratory analysis of tumor immune features (as previously reported25) linked to MHC-I/II expression across races would be of potential future interest to the translational field as well. Finally, while we investigated MHC expression as a biomarker in this study, we acknowledge that other useful markers may also be important upstream or downstream pathway members26.
Conclusions:
In this diverse breast cancer cohort, MHC-I and MHC-II tumor cell expression, candidate predictive biomarkers of IO benefit, were more prevalent in tumors from Black women with HR+/HER2− breast cancer. These results underscore the importance of diverse and equitable clinical trial enrollment in future IO trials, especially in HR+/HER2− breast cancer.
Supplementary Material
Acknowledgements
This work was supported by funds from the NCI Breast SPORE program (P50-CA058223; MT and CMP and P50CA098131; JMB and SAR), by the Breast Cancer Research Foundation, and by the Susan G. Komen.
Footnotes
Conflict of Interests
Justin Balko receives research support from Genentech/Roche and Incyte Corporation, has received advisory board payments from AstraZeneca, Eli Lilly, and Mallinckrodt and is an inventor on patents regarding immunotherapy targets and biomarkers in cancer. Charles M. Perou is an equity stockholder and consultant of BioClassifier LLC; Charles M. Perou is also listed as an inventor on patent applications for the Breast PAM50 Subtyping assay. Laura C. Kennedy has research support from Puma Biotechnologies and Hoffmann-Roche and consulting fees from Daiichi-Sankyo. The other authors disclosed no conflicts of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Existing CBCS data are available upon request (https://unclineberger.org/cbcs). MHC-I, MHC-II quantification and images, as well as an R code/script for data analysis is available upon email request to justin.balko@vumc.org.